Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis, collectively referred to as 'phosphatonins.' We identified the phosphatonin Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. The FGF23 co-receptor ?Klotho (?KL), acting in a heteromeric complex with a canonical FGF receptor (FGFR), is required for normal phosphate metabolism. This is emphasized by the fact that ?KL loss of function mutations lead to end organ Fgf23 resistance, and cause the phenotypic reciprocal disorder to ADHR, familial hyperphosphatemic tumoral calcinosis (TC). ?KL is expressed as a membrane-bound protein (mKL) that mediates Fgf23-dependent signaling in target tissues, as well as a major circulating species that originates from the proteolytic cleavage of mKL within its juxta extracellular membrane domain to derive 'cKL'. The biological activity of the cKL species is unknown. The novel preliminary studies presented herein make important, mechanistic connections regarding the regulation of Fgf23 production, and significantly modify the current models explaining phosphate homeostasis. In this regard, cKL delivery to wild type mice potently stimulates bone Fgf23 mRNA production, leading to highly elevated serum Fgf23. The treated animals manifest severe hypophosphatemia, alterations in renal 1,25(OH)2 vitamin D production pathways and hyperparathyroidism, with reduced bone mineral content and fractures. Further, blood cKL concentrations in vivo are correlated with changes in phosphate metabolism, and cKL demonstrates FGFR-dependent activity. Of significance, the mice treated with cKL are biological phenocopies of a patient with an ?Klotho gene translocation (t9:13), that resulted in markedly increased serum cKL concentrations. Collectively, these new findings demonstrate that the molecular mechanisms dictating Fgf23 production, as well as the control of Fgf23 bioactivity and expression via the ?KL isoforms remain to be defined. Thus, the central hypothesis to be tested is: the cKL form of ?KL controls an endocrine homeostatic axis between FGF23 target tissues and the skeleton by stimulating Fgf23 production. We expect our studies will provide novel, translational insight into rare, and common syndromes of altered FGF23 expression such as CKD-MBD, and into the basic biology of phosphate metabolism.